1. Introduction

Heart failure (HF) is the leading cardiovascular disease, affecting approximately 26 million people worldwide ^[1][2][1,2]. Fortunately, in the last 30 years, the knowledge of the pathophysiology of this clinical syndrome has developed considerably, leading to the identification of drugs which can significantly improve the prognosis of these patients, called disease-modifying drugs ^[3][4][5][3,4,5].

Among them, β-blockers are indicated by international guidelines as the cornerstone of therapy for patients with HF with reduced ejection fraction (HFrEF) ^[6][7][8][6,7,8]. The optimal use of β-blockers has been shown to improve symptoms, reduce hospitalizations, induce left ventricular reverse remodelling, and increase survival in HFrEF patients ^[9][10][9,10]. Despite the proven benefit of β-blockers in chronic HF, they are often underutilized in current clinical practice ^[11][12][11,12]. There are a lot of well written reviews on the use of β-blockers in HFrEF; however, they only partially analyze the clinical aspects regarding this matter. To allow a proper diffusion of knowledge about the correct use of β-blockers, in this review we analyze the rationale and scientific evidence for the use of this drug in HFrEF patients with and without comorbidities, as well as provide practical tips for clinical cardiologists about the use of these drugs in the management of these patients.

2. Use of β-Blockers in HFrEF: Pathophysiology and Clinical Pharmacology

After a myocardial insult—whether acute (e.g., myocardial infarction or myocarditis) or chronic (e.g., hypertension or mitral valve insufficiency), which results in left ventricular dysfunction—the renin–angiotensin–aldosterone system and the sympathetic nervous system (SNS) are hyperactivated ^[13][14][13,14]. Persistent activation of the SNS in patients with HFrEF is evidenced by increased plasma levels of epinephrine and norepinephrine [15] and an increased spillover of the latter from sympathetic nerve endings into the bloodstream [16]. This increase in the catecholamines release leads to chronic and persistent stimulation of myocardial β-receptors, with consequent dysfunction and harmful repercussions for the failing heart ^[17][18][17,18].

Clinical consequences of these processes consist of reduced systolic function and left ventricular ejection fraction, acceleration of the left ventricular remodelling process, and the appearance of life-threatening ventricular arrhythmias ^[19][24].

All this action leads to improvements in the structure and function of the left ventricle (reverse remodelling). Other beneficial activities in patients with HFrEF include reducing heart rate ^[20][28] and blood pressure, reducing the burden of atrial and ventricular arrhythmias ^[21][29], and anti-ischaemic effects ^[22][30]. Moreover, β-blockers improve the contractility of viable but noncontractile myocardium in patients with ischaemic (hibernating myocardium) ^[23][31] and non-ischaemic (stunning myocardium) HFrEF ^[24][32].

β-blockers can be broadly classified ^[25][33] into: (1) Nonselective β-blockers with similar β1 and β2 activity (none of the β-blockers belonging to this class is indicated for HFrEF); (2) β1-selective with a higher affinity for β1-adrenoreceptors (metoprolol, bisoprolol, and nebivolol), preferred in patients with chronic obstructive pulmonary disease or mild asthma (nebivolol also facilitates nitric oxide release and is preferred in patients with arterial hypertension); (3) β-blockers with additional α-1-adrenoreceptor antagonism and consequent peripheral vasodilation (carvedilol), preferred in patients with hypertension or documented higher peripheral vascular resistance.

3. Evidence Supporting the Use of β-Blockers in HFrEF

The activation of the SNS is one of the significant pathophysiological abnormalities in HFrEF patients. Since the 1970s, it has been known that patients with HFrEF have higher plasmatic norepinephrine levels and that prognosis is directly related to catecholamine plasma levels. However, the first multicenter randomized trial was not conducted until the early 1990s, and carvedilol was approved for the treatment of HFrEF only in 1997. The reason for such a slow acceptance of the use of β-blocker therapy for HFrEF was the transient negative inotropic effect of the β-blockade and the subsequent risk of decompensation in patients with HFrEF.

Carvedilol: The 1996 U.S. Carvedilol Heart Failure Study enrolled 1094 HF patients with FE < 35%; 696 patients were treated with carvedilol (target dose: 25–50 mg twice daily), 398 with placebo ^[26][37]. The study was stopped early because carvedilol therapy was accompanied by a 27% reduction in the risk of hospitalization for cardiovascular causes (19.6% vs. 14.1%, p = 0.036), as well as a 38% reduction in the combined risk of hospitalization or death (24.6% vs. 15.8%, p < 0.001). In the randomized multicenter trial Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN), the effects of carvedilol on morbidity and mortality in patients with prior myocardial infarction and EF < 40% were evaluated. The trial enrolled 1959 patients, randomly assigned to receive carvedilol ( n = 975) or placebo ( n = 984). The study demonstrated reduced cardiovascular and non-cardiovascular mortality in patients in the carvedilol group (12% vs. 15%, hazard ratio 0.77 (95% CI 0.60–098), p = 0.03) ^[27][38].

In the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study, 2289 patients with advanced HF and EF < 25% were randomized to receive carvedilol or placebo. After an average follow-up period of 10.4 months, mortality was reduced by 34% in the carvedilol group ^[28][39]. Carvedilol also reduced the number of days spent in hospital by 27% for any cause and by 40% for heart failure. Patients in the carvedilol group felt better and were less likely to have a severe adverse event related to HF.

Bisoprolol: In the trial Cardiac Insufficiency Bisoprolol Study I (CIBIS-I), 641 patients with HF and EF < 40% were randomly assigned to bisoprolol or placebo groups ^[29][40]. The observed difference in mortality between groups did not reach statistical significance (relative risk, 0.80; (95% CI 0.56–1.15), p = 0.22); however, bisoprolol significantly improved the New York Heart Association (NYHA) class ( p = 0.04). In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), 2647 patients with symptomatic HF (NYHA class III–IV) and EF < 35% were randomly assigned to receive bisoprolol or placebo ^[30][41]. The trial was stopped after the second interim analysis because bisoprolol showed a significant mortality benefit. All-cause mortality was significantly lower with bisoprolol than placebo (11.8% vs. 17.3%, hazard ratio of 0.66 (95% CI 0.54–0.81) p < 0.0001); there were also significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (3.6% vs. 83 6.3%, hazard ratio of 0.56 (95% CI 0.39–0.80), p = 0.0011).

4. Use of β-Blockers in Patients with Heart Failure and Comorbidities: A Practical Approach

Comorbidities are highly prevalent in patients with HFrEF with a significant impact on disease progression and long-term prognosis ^[31][52]. Recent evidence shows that, in patients with HFrEF and multiple comorbidities, β-blockers are still able to achieve favorable prognostic effects ^[32][53]. Therefore, the optimization of β-blockers therapy and the appropriate selection of the best suited β-blocker ( Table 13 ) is of paramount importance in this specific subgroup of patients.

Table 1. Choice of β-blockers according to clinical scenario.

The use of β-blockers in patients with HFrEF and diabetes has historically been controversial ^[33][61]. The main reason for concern is the negative effect of β-blockers on glucose metabolism. Indeed, β-blockers might contribute to the development of hyperglycaemia by impairing the release of insulin from pancreatic β-cells ^[34][62]. In addition, β-blockers may mask the catecholamine-mediated symptoms of hypoglycaemia ^[35][63]. An analysis of six pivotal β-blocker trials, including 3230 patients with diabetes, showed that β-blockers significantly reduced mortality in individuals with (relative risk: 0.84 (95% CI 0.73–0.91)) and without (relative risk: 0.72 (95% CI 0.65–0.79)) diabetes ^[36][64]. Furthermore, concerns about worsening glycaemic control in patients with type 2 DM treated with β-blockers seem unfounded; in a recent study, in which 125 diabetic patients were enrolled, the use of carvedilol or bisoprolol did not worsen glycaemic control ^[37][65]. Therefore, the use of β-blockers should not be avoided in patients with HFrEF and diabetes. Carvedilol and bisoprolol should be used preferentially because they do not adversely affect the patients’ glycaemic profile.

These data, like real-world data, document a prognostic advantage of β-blockers in all patients with HFrEF regardless of the presence of atrial fibrillation. Another important question is to what level of mean ventricular rate the patient with HFrEF and atrial fibrillation should be taken. The European Society of Cardiology guidelines state that the optimal resting heart rate in patients with AF and HF is unknown but may be between 60 and 100 beats per minute ^[38][69]. Randomized clinical trials that may clarify the optimal resting ventricular rate in patients with HFrEF and atrial fibrillation are pending, but it is the authors’ opinion that excessive rate control, associated with increased pauses, poses a risk in such patients. The use of β-blockers in these patients should therefore not be aimed at reaching target doses but at achieving a mean ventricular frequency of 70–80 beats/min to avoid prognostically unfavorable effects.

In conclusion, therapy with β-blockers can be safely conducted in patients with peripheral artery disease, in cases of severe intermittent claudication preferring those with vasodilation activity, such as carvedilol and nebivolol.